The epidermal growth factor (EGF) receptor is transmembrane glycoprotein with tyrosine-kinase activity. In most of the cell types which have been studied, EGF produces a mitogenic response. EGF has been shown to bind to osteoblastic cells in vivo and vitro. In bone organ culture systems, EGF produces increased bone resorption, increased PGE2 production and decreased collagen synthesis. EGF was also found to increase PGE2 production in osteosarcoma cell lines as well as primary culture cells from chick calvaria. In our laboratory we have shown that EGF increases cell proliferation in the G292 cell line and in primary culture osteoblasts isolated from neonatal rat calvaria. The mechanisms by which tyrosine-kinase receptors produce their response in bone cells has not been characterized. We have done proliferation studies using a variety of second messenger inhibitors, as well as pertussis toxin which inactivates G(i) proteins, in order to dissect the cascade of events which results in the EGF mitogenic response in G292 and primary culture osteoblasts. Data from our lab suggest that the role of various second messengers in the EGF proliferative response are different for G292 and primary culture cells. It is our goal to further explore the differences between the two cell types. In addition we are interested in the role of EGF on the electrophysiology of osteoblastic cells. There is evidence in the A431 human epidermoid carcinoma cell that EGF, in a tyrosine-kinase dependent fashion, can regulate Ca2+ channels. We are planning to look at the role of EGF in regulation of ion channels in osteoblasts. It is the aim of our studies to continue the investigation of events involved in the osteoblastic response to EGF. In summary, these studies will enhance our understanding of bone resorption resulting from activation of a tyrosine-kinase receptor in osteoblastic cells. Key Words: osteoblasts, epidermal growth factor, bone resorption, mitogenesis